Metformin, a biguanide, is used as first-line therapy to treat type 2 diabetes (T2D), yet over 35% of patients on metformin monotherapy fail to achieve acceptable glycemic control. In addition, studies indicate that there are profound inter-ethnic differences in the pharmacokinetics and pharmacodynamics of metformin, and that genetic factors contribute to metformin response. To date, there has been only a single published genomewide association study (GWAS) of metformin response in Europeans, and no GWAS in other ethnic The major goal of our study is to identify the genetic loci and pathways that confer nonresponse to metformin in a large multi-ethnic cohort of T2D patients on metformin. Our second goal is to identify rare causal variants that underlie variation in response to metformin through detailed cellular and clinical studies. To this end, we have assembled rich and diverse clinical cohorts including two groups. large multi-ethnic cohorts of patients with T2D on metformin who have provided DNA samples and clinical information (N = 15,000) made available largely through partnerships with the Kaiser Permanente Northern California (KPNC) Research Program on Genes, Environment and Health (RPGEH) and MetGen, an international consortium, which includes multiple cohorts from Europe and the U.S. of patients on metformin (N ~ 10,000). Our overall aims are to: Aim 1. Identify genetic variants that impact response to metformin in 28,000 participants from multiple ethnic groups in the U.S. and Europe; and Aim 2. Identify the causal variants of genes discovered in Aim 1, using a multi-tier approach. In particular, we will first use genomewide approaches with meta analyses to discover variants that underlie variation in response to metformin. Next targeted resequencing will be used to associate rare variants in genes that are identified in our GWAS with metformin response. Functional genomic studies in cells will be performed to identify functional variants, which will then be associated with metformin response in our clinical cohorts. Finally, in Aim 3, we will conduct endophenotypic clinical studies to determine clinical measurements of insulin sensitivity and glucose tolerance to understand the mechanisms through which the variants modulate metformin response. Collectively, this research proposal provides a robust multi-tier approach beginning with the largest cohort of patients with T2D on metformin to identify rare and common genetic variants that underlie variation in response to metformin and importantly, to understand their mechanisms. Data generated in this project will contribute enormously to predictive models that ultimately will be used for data-driven prescribing and precision medicine for anti- diabetic drug therapy.